Updated MARIPOSA Data Highlight Clinical Impact of Upfront Dual Inhibition in EGFR+ NSCLC

The treatment of non–small cell lung cancer (NSCLC) harboring EGFR mutations has transformed with the introduction of targeted therapies. Despite the success of third-generation tyrosine kinase inhibitors (TKIs) such as osimertinib (Tagrisso; AstraZeneca), acquired resistance remains a challenge for most patients, limiting the durability of responses and ultimately driving disease progression.1

Against this backdrop, updated findings from the phase 3 MARIPOSA trial (NCT04487080) were presented at the 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, highlighting the potential of a dual-targeted strategy using the bispecific antibody amivantamab (Rybrevant; Janssen Biotech) in combination with the third-generation TKI lazertinib (Lazcluze; Janssen Biotech).1,2 The data show that this combination significantly reduces the emergence of resistance mechanisms compared with osimertinib, while also extending survival in patients with EGFR exon 19 deletions (ex19del) or exon 21 L858R substitution mutations.1

Background and Rationale

EGFR mutations are among the most clinically actionable molecular drivers in NSCLC, occurring in approximately 10% to 15% of patients in Western populations and 40% to 50% in Asian populations. The most common variants, ex19del and L858R, account for the majority of cases. First- and second-generation TKIs initially demonstrated the value of EGFR-targeted therapy; however, resistance consistently developed.1

Amivantamab, a fully human bispecific antibody targeting EGFR and MET, provides an immune cell–directing mechanism of action distinct from that of TKIs. | Image Credit: © Goody ART - stock.adobe.com

The advent of third-generation TKIs, such as osimertinib, addressed resistance mediated by the T790M mutation and improved progression-free survival (PFS) and central nervous system penetration; however, acquired resistance to osimertinib frequently arises through alternative EGFR mutations, such as C797S, and via bypass signaling through MET amplification, leaving an unmet need for more durable frontline strategies.1

Amivantamab, a fully human bispecific antibody targeting EGFR and MET, provides an immune cell–directing mechanism of action distinct from that of TKIs. Lazertinib, a brain-penetrant third-generation EGFR TKI, complements this approach by inhibiting activating EGFR mutations and T790M while sparing wild-type EGFR.1 In the MARIPOSA study, investigators designed the trial to assess whether dual inhibition of EGFR and MET could prevent the emergence of resistance, prolong survival, and establish a new standard of care in EGFR-mutated NSCLC.1,2

Study Design and Methods

MARIPOSA is a randomized, phase 3 trial that enrolled 1074 patients with locally advanced or metastatic NSCLC harboring ex19del or L858R EGFR mutations.1,2 Patients were randomized to receive 1 of 3 regimens: amivantamab plus lazertinib, osimertinib, or lazertinib monotherapy. The primary end point was PFS, assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were overall survival (OS), overall response rate, duration of response, PFS after first subsequent therapy, and intracranial PFS.1

OS data from MARIPOSA reported earlier in 2025 demonstrated that amivantamab plus lazertinib conferred a survival advantage over osimertinib, with a projected median OS exceeding 4 years compared with approximately 3 years on osimertinib monotherapy. The updated analyses presented at WCLC 2025 focused on mechanisms of acquired resistance to therapy.1

Key Findings on Resistance Mechanisms

MARIPOSA data demonstrate that the combination of amivantamab plus lazertinib impacts the development of resistance in EGFR-mutated NSCLC. Among patients treated with osimertinib, MET amplification occurred in 13%, while EGFR secondary mutations, including C797S, emerged in 8%. By contrast, 3% of patients receiving amivantamab plus lazertinib developed MET amplification and just 1% developed secondary EGFR mutations. Both differences were statistically significant (P = .002 for MET; P = .01 for EGFR).1

Furthermore, the timing of resistance events differed meaningfully between arms. Acquired MET amplification led to early treatment discontinuation within 6 months in 23% of patients on osimertinib compared with only 4% of those on the combination. Among patients who remained on amivantamab plus lazertinib for at least 6 months, resistance was exceedingly rare, with only 2% developing MET amplification and no cases of C797S reported.1

In addition to lower frequencies of resistance, the spectrum of resistance mechanisms was narrower in the combination arm. Patients treated with osimertinib exhibited greater overall genetic diversity of resistance pathways, including multiple EGFR- and MET-based alterations. This finding underscores the potential of upfront dual blockade to extend therapeutic benefit.1

According to Sanjay Popat, FRCP, PhD, medical oncologist at the Royal Marsden Hospital and the Institute of Cancer Research at Imperial College in the United Kingdom, these results support the growing recognition that TKI monotherapy may no longer be sufficient in the frontline setting for EGFR-mutated NSCLC.1

"We now have a body of evidence that suggests TKI monotherapy is no longer enough in the first-line treatment of EGFR-mutated lung cancer," said Popat. "The MARIPOSA results show that combining amivantamab with lazertinib is an important step forward, reducing EGFR-and MET-driven resistance seen with TKI-based therapy and giving patients a longer, stronger first response."1

From a clinical perspective, the ability to delay or prevent resistance is highly significant. The choice of initial therapy in EGFR-mutated NSCLC not only dictates immediate disease control but also influences the trajectory of resistance and available subsequent treatment options. By reducing the likelihood of resistance mutations such as C797S and MET amplification, amivantamab plus lazertinib preserves therapeutic flexibility and may extend the OS horizon for these patients.1

Safety and Tolerability

The safety profile of amivantamab plus lazertinib was consistent with prior analyses and aligned with expectations for each agent’s known toxicity profile. Most grade 3 or higher adverse events (AEs) occurred during treatment initiation. Common toxicities included dermatologic reactions, infusion-related reactions (IRRs), and venous thromboembolic events. Importantly, no new safety signals emerged with longer follow-up, suggesting the regimen is manageable with appropriate supportive care and prophylactic measures.1

Several strategies have been explored to mitigate AEs. For example, prophylactic dermatologic interventions and premedication protocols have demonstrated success in reducing the incidence and severity of skin toxicities and IRRs, respectively. Ongoing studies such as COCOON (NCT06120140) and SKIPPirr (NCT05663866) are further refining approaches to supportive care in this population.1,3,4

Regulatory and Guideline Status

Based on the MARIPOSA trial, amivantamab plus lazertinib has been approved in the US, Europe, and other global markets as a first-line treatment for patients with EGFR ex19del– or L858R-mutated advanced NSCLC.5 The National Comprehensive Cancer Network guidelines now list the combination as a category 1 recommendation in this setting, reflecting its evidence-based role as a preferred standard of care. Additionally, the regimen has category 1 endorsement for patients progressing on osimertinib when given with chemotherapy and for patients with exon 20 insertion mutations in combination with chemotherapy.1

Broader Context in EGFR-Mutated NSCLC

The MARIPOSA trial is part of a broader wave of studies investigating amivantamab across multiple EGFR-driven NSCLC subgroups and treatment settings. MARIPOSA-2 (NCT04988295) is evaluating amivantamab (with or without lazertinib) plus chemotherapy vs chemotherapy alone in patients who progressed on osimertinib.6 PAPILLON (NCT04538664) is examining amivantamab plus chemotherapy in exon 20 insertion–positive NSCLC, while the PALOMA program is investigating subcutaneous formulations of amivantamab to improve convenience and tolerability.1,7 Together, these efforts reflect a comprehensive strategy to integrate dual EGFR and MET blockade across the disease continuum.1

References

1. Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) prevents acquiredresistance versus osimertinib in first-lineEGFR-mutated non-small cell lung cancer. News release. Johnson & Johnson. September 6, 2025. Accessed September 8, 2025. https://www.prnewswire.com/news-releases/rybrevant-amivantamab-vmjw-plus-lazcluze-lazertinib-prevents-acquired-resistance-versus-osimertinib-in-first-line-egfr-mutated-non-small-cell-lung-cancer-302548296.html
2. Aamivantamab and lazertinib combination therapy versus osimertinib in locally advanced or metastatic non-small cell lung cancer (MARIPOSA). Clinicaltrials.gov. Updated August 19, 2025. Accessed September 8, 2025. https://www.clinicaltrials.gov/study/NCT04487080
3. Enhanced dermatological care to reduce rash and paronychia in epidermal growth factor receptor (EGRF)-Mutated non-small cell lung cancer (NSCLC) treated first-line with amivantamab plus lazertinib (COCOON). Clinicaltrials.gov. Updated August 26, 2025. Accessed September 10, 2025. https://www.clinicaltrials.gov/study/NCT06120140
4. Premedication to reduce amivantamab associated infusion related reactions. Clinicaltrials.gov. Updated May 25, 2025. Accessed September 10, 2025. https://www.clinicaltrials.gov/study/NCT05663866
5. FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. News release. FDA. Updated August 20, 2024. Accessed September 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer
6. A study of amivantamab and lazertinib in combination with platinum-based chemotherapy compared with platinum-based chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer after osimertinib failure (MARIPOSA-2). Clinicaltrials.gov. Updated August 19, 2025. Accessed September 10, 2025. https://clinicaltrials.gov/study/NCT04988295
7. A Study of combination amivantamab and carboplatin-pemetrexed therapy, compared with carboplatin-pemetrexed, in participants with advanced or metastatic non-small cell lung cancer characterized by epidermal growth factor receptor (EGFR) exon 20 insertions (PAPILLON). Clinicaltrials.gov. August 19, 2025. Accessed September 10, 2025. https://www.clinicaltrials.gov/study/NCT04538664